Antiseptics are agents designed to kill microbes on exposed surfaces. They are used to prepare the skin for minor and major surgical procedures, to sterilize inanimate articles, operating rooms, hospital environments and for the disinfection of water.
Antiseptics applied to animate bodies are called antiseptics, bactericides, or bacteriostats; those applied to inanimate bodies are called disinfectants or germicides.
Halogen compounds have been used for a long time as antiseptics and disinfectants. Their action and mechanism is exerted by interfering with enzymes and coagulating protein. They are more potent than most local antiseptics.
Among long established preparations are: chloramine T, chloroazodin, Iodoform, tincture of iodine, sodium hypochlorite, hexachlorophene, betadine and halazone. Well-known antibacterial agents that contain chlorine bound to nitrogen are: chloramine T, dichloramine T and halazone. The last compound has been widely used for water disinfection.
None of these N-chloro compounds is a real chloramine in the strict chemical sense; rather, it is a chlorosulfonamide.
Other N-chloro compounds that have been used (or proposed) as antiseptics are the cyclic imides and amidines (see Burger's Medicinal Chemistry, 6th Ed., Part III, Chapter 14).
The present invention relates to novel chloroamino acids which are stable, non-toxic, economic and potent antibacterial agents. Unlike the widely used topical antiseptics such as hexachlorophene and chlorohexidine, these novel chloroamines are non-persistent, i.e., after accomplishing their germicidal or fungicidal action, they are converted into safe, non-toxic materials. Furthermore, they are shown by skin irritation tests to be totally non-irritating in concentration of 1% (10.sup.4 ppm). This result is significant as the novel compounds of this invention are active as fungicidal or germicidal agents at concentrations as low as 100 ppm.
Preliminary formulation studies show that the new chloramines are remarkably stable in certain solvents. For example, 2-dichloroamino-2-methyl-1-propyl hemisuccinate showed no decomposition in esters of polyalcohols such as Triacetin at 60.degree. C. for two months. Triacetin is the triacetate of glycerin; it is a viscous liquid with high water solubility and very low toxicity. A concentrated solution of the chloramine in Triacetin suggests itself as a simple, stable antimicrobial product. Of course other aprotic polar solvents can be used as well.
It is desirable that topical antiseptics conform with the following criteria:
(1) the antiseptic should have a broad range of activity against Gram-negative and Gram-positive organisms at low concentrations;
(2) the antiseptic should retain its activity in the presence of soap and protein;
(3) the antiseptic should be non-irritating;
(4) the antiseptic should be stable neat and in solution;
(5) the antiseptic should be non-toxic. The new chloramines of this invention meet all of the above criteria. On the contrary, from a comparative study, all of the products in commercial use fail to meet one or more of the above requirements. Quaternary ammonium compounds are quite active against Gram-positive and Gram-negative organisms but they are easily deactivated by soap and serum. Alcohol, iodine (Betadine), mercurials and silver nitrate tend to irritate and injure the skin. Hexachlorophene is the most widely used phenolic compound employed to disinfect skin and it is compatible with soap. However, it is ineffective against Gram-negative organisms and in animal tests has caused neurotoxicity. Chlorhexidine is a bisguanidine which is generally effective against Gram-positive and Gram-negative oganisms but is deactivated by soap and salts (chlorides, borates, phosphates and sulphate), can cause skin irritation and is not effective against pseudomonas organisms. Chlorine, bromine and iodine are effective antimicrobials but they are irritating and difficult to handle because of their lack of stability.
Alkylcarboxyl derivatives of N-chloroamino alcohols such as 2-chloroamino-2-methyl-1-propyl acetate, i.e., ##STR1## and related compounds are known (U.S. Pat. No. 4,171,452) as antibacterial and antifungal agents in mouth washes. However, they are distinguishable from the N,N-dichloroamino acid derivatives of the present invention by lacking the carboxylic acid function which give the novel compounds of the present invention the following important characteristics:
(1) Increased water solubility;
(2) Partition coefficients having values close to unity which is a value that is very favorable for skin penetration. This ability to penetrate into the skin coupled to high germicidal and fungicidal activity can be exploited in the treatment of acne and topical fungal diseases; and
(3) Enhanced germicidal activity. For example, .beta.-dichloroamino-isovaleric acid retains germicidal activity at a concentration of merely 5 ppm or lower.